@ 2021 EDIZIONI MINERVA MEDICA Online version at https://www.minervamedica.it REVIEW Mitotane treatment in adrenocortical carcinoma: mechanisms of action and predictive markers of response to therapy Barbara ALTIERI 1 *, Enzo LALLI 2, 3, 4, Antongiulio FAGGIANO 5 ABSTRACT Adrenocortical carcinoma (ACC) is a rare malignancy with a high risk of recurrence even in cases with complete surgical tumor resection. Mitotane represents the cornerstone of the adjuvant therapy as well as the first line of medical treat- ment in advanced cases. However, evidence on mitotane efficacy is mostly based on retrospective studies and the use of mitotane continues to represent a clinical challenge. Mitotane causes selective damage to adrenocortical cells, causing an increase of cell apoptosis through a disruption of mitochondria and the induction of the endoplasmic reticulum stress. Different clinical and molecular markers predicting response to mitotane have been proposed with uncertain results. Attainment of mitotane plasma levels within the target range of 14 to 20 mg/L represent the strongest predictor of mi- totane effectiveness both in adjuvant and advanced tumor setting. The occurrence of late recurrence after primary ACC diagnosis and changes in metabolic activity on FDG-PET are only weakly associated with mitotane response. Among the proposed molecular markers associated with mitotane efficacy, the investigation of the CYP2W1*6 and CYP2B6*6 single nucleotide polymorphisms appears to be currently the most promising predictive molecular markers of mitotane therapy. However, none of the evaluated markers has been validated for clinical use. In the era of precision medicine, a better insight into mitotane molecular mechanisms as well as the potential use in the daily clinical practice of clinical parameters and molecular markers predicting the individual response to mitotane are urgently needed. A drenocortical carcinoma (ACC) is a rare ma- lignancy with an annual incidence of 0.7-2.0 cases per million per year that can occur at any age, with a peak of incidence in the fifth decade and with women more affected than men.1, 2 Ste- roid hormone excess, which may result in differ- ent endocrine syndromes, can be found in up to 60% of ACC patients, whereas a smaller propor- tion of cases present with symptoms associated with tumor mass.3 ACC is an aggressive tumor Vol. 47 - No. 2 MINERVA ENDOCRINOLOGY cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher. (Cite this article as: Altieri B, Lalli E, Faggiano A. Mitotane treatment in adrenocortical carcinoma: mechanisms of action and predictive markers of response to therapy. Minerva Endocrinol 2022;47:203-14. DOI: 10.23736/S2724-6507.21.03601-0) KEY WORDS: Adrenocortical carcinoma; Mitotane; CYP2W1 protein, human; CYP2B6 protein, human; Sterol O-acyl- transferase 1.
1Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany; 2Institute of Molecular and Cellular Pharmacology CNRS UMR, Valbonne, France; 3University of Côte d’Azur, Valbonne, France; 4INSERM, Valbonne, France; 5Unit of Endocrinology, Department of Clinical and Molecular Medicine, Sant’ Andrea Hospital, Sapienza University, Rome, Italy.
*Corresponding author: Barbara Altieri, Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital of Würzburg, Oberduerrbacher-Str 6, 97080 Würzburg, Germany. E-mail: Altieri_B@ukw.de
with a heterogeneous prognosis mostly depen- dent on the European Network for the Study of Adrenal Tumors (ENSAT) tumor stage, with a 5-years survival ranging from 80% in localized disease to 15% in advanced cases.4 However, ACC prognosis may be influenced also by mo- lecular5-8 and pathological markers,9-12 as well as by different clinical parameters, including resection status, Ki-67 index, age, and cortisol secretion.13-18 Although the molecular mecha-
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MITOTANE TREATMENT IN ADRENOCORTICAL CARCINOMA
ALTIERI
nisms underlying the pathogenesis of ACC has significantly improved in recent years,5-7, 19 our knowledge remains not satisfactory.20-23 The two most frequent alterations reported in ACC are the alteration of the insulin like growth factor (IGF) pathway, characterized by an overexpression of IGF-2,11, 24-27 and a constitutive activation of the Wnt/B-catenin pathway.5, 7, 28 The therapeu- tic options available for ACC are limited29, 30 and a complete surgical tumor resection, when feasible, represents the only curative option for ACC patients.3, 31 However, even in case of a complete tumor resection, more than half of cases presents recurrence,32-34 providing a strong rationale for the use of adjuvant treatment fol- lowing ACC surgical removal.3, 31 Although mi- totane (1-[2-chlorophenyl]-1-[4-chlorophenyl]- 2,2-dichloroethane, [o,p’-DDD]) is approved by the Food and Drug Administration and by the European Medicines Agency for the treatment of advanced ACC, its use represents the most common approach in adjuvant settings of ACC patients in the daily clinical practice.29 However, the use of adjuvant mitotane remains a matter of controversy because the evidence supporting its efficacy derives from retrospective studies only, potentially biased by confounding factors such as limited number of patients, absence of a control group, and use of different regimes of drug ad- ministration.3 The best evidence supporting the use of adjuvant mitotane derives from the larg- est retrospective, multicenter, case-control study by Terzolo et al.,35 which demonstrated that patients treated adjuvantly with mitotane had a significantly improved recurrence-free survival (RFS) compared to two different control groups The association of adjuvant mitotane treatment with a prolonged RFS and overall survival (OS) after tumor resection was also confirmed by a meta-analysis.36 The recent European Society of Endocrinology (ESE)-ENSAT guidelines sug- gest adjuvant mitotane therapy in patients with a high risk of recurrence (ENSAT tumor stage III, or microscopic residual tumor [R1 resection], or Ki67>10%) following radical surgery.3, 37 The question whether mitotane is of benefit for pa- tients with low-intermediate risk of recurrence (ENSAT tumor stage I-II, complete tumor re- section [RO resection] and Ki67≤10%) was very
recently addressed by the first randomized con- trolled phase III trials (ADIUVO, ClinicalTrials. gov Identifier: NCT00777244), which compared the efficacy of adjuvant mitotane treatment vs. observation in prolonging RFS in this subgroup of patients.38 The preliminary results demonstrat- ed that RFS and OS did not significantly differ between the mitotane adjuvant and the observa- tional arms, underlying that this subgroup of ACC patients presented a good prognosis (5-years RFS of 75%) independently from adjuvant mitotane.38 Therefore, these results did not support the use of adjuvant mitotane in ACC patients with low- intermediate risk of recurrence, who may thus avoid a potentially toxic treatment. A second pro- spective, randomized study on adjuvant therapy in high-risk patients (ADIUVO-2, ClinicalTrials. gov Identifier: NCT03583710) comparing the efficacy of mitotane vs. mitotane plus cisplatin and etoposide in preventing ACC recurrence is currently ongoing. On the other hand, the use of mitotane in patients with advanced (unresectable, metastatic or relapsed) ACC, alone as monother- apy in low-grade disease with limited metastatic burden,39, 40 or in combination with cytotoxic chemotherapy in case of or patients with highly proliferating and widespread disease,29, 41-43 is currently recommended as first-line therapy.3, 31 Particularly, a large retrospective study investi- gating the efficacy of mitotane monotherapy in advanced ACC showed that 20.5% of patients experienced objective response.39 Although its proved efficacy in ACC, the treatment with mi- totane continues to represent a clinical challenge more than sixty years after its introduction in the clinic. Indeed, several points regarding its precise mechanism of action, the optimal duration of the therapy as well as the optimal balance between efficacy and toxicity are still not entirely clear. In this review we aim to summarize the current evidence on mitotane treatment, with a particular focus on the most recent finding and predictive markers of response to therapy.
Mechanisms of action and metabolism of mitotane
Mitotane is a derivate of the insecticide dichlo- rodiphenyltrichloroethane (DDT). The adre-
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MITOTANE TREATMENT IN ADRENOCORTICAL CARCINOMA
Direct cytotoxic effect on adrenocortical cells
Inhibition of steroiodgenesis
mitotane
Cholesterol
StAR
CYP11A1
CYP17A1 (17a-hydroxylase)
CYP17A1 (17, 20 lyase)
SOAT1
Pregnenolone
17a-OH Pregnenolone
DHEA
ER stress
HSD3B2
CYP17A1 (17a-hydroxylase)
HSD3B2
CYP17A1 (17, 20 lyase)
HSD3B2
FA f Chol 1 FA t Chol
Caspase 3/7
Progesterone
17a-OH Progesterone
Androstenedione
1 CHOP
BAX Bcl2
CYP21A2
CYP21A2
17ß-OH
11-deoxycorticosterone
11-deoxycortisol
Testosterone
CYP11B1
CYP11B1
SREBF
XBP1
Cortisol
1 Cell apoptosis
Corticosterone
CYP11B2
t Steroidogenesis
Symbol legend:
Inhibition by mitotane Inhibition by mitotane demonstrated only from single evidence
Aldosterone
A
B
nolytic activity of DDT derivates was first de- scribed in dogs in 1940s;44 however, despite 60 years of use, the basis for its action has yet to be convincingly established.45, 46 Mitotane has two main biological effect: 1) direct cytotoxic effect on adrenocortical cells and 2) inhibition of ste- roidogenesis (Figure 1). It has been demonstrat- ed that the administration of mitotane results in destruction of zona fasciculata and zona retic- ularis of the adrenal cortex.45 In the ACC cell line NCI-H295R, mitotane rapidly accumulated intracellularly in a dose- and time-dependent manner, with an impact on cell viability and pro- liferation and an increase of apoptosis.47, 48 This direct cytotoxic effect on ACC cells is mediated by mitochondrial damage,48 which activates the apoptotic process through caspase 3 and 7,47 and by the inhibition of sterol-O-acyl transferase 1 (SOATI) (Figure 1A).49 Particularly, Sbiera et al. identified SOAT1 as the key molecular target
of mitotane action.49 SOAT1 is an intracellular protein expressed in the endoplasmic reticulum (ER) that regulates the formation of fatty acid and free cholesterol (Figure 1A).50 The inhibi- tion of SOAT1 by mitotane is associated with an intracellular accumulation of fatty acid-cho- lesterol ester that induces ER stress.49 ER stress stimulates the transcription factor X-box-bind- ing protein 1 (XBPI) that upregulates different genes, including the C/EBP homologous protein (CHOP, also known as DNA damage-inducible transcript 3 - DDIT3).51 The upregulation of CHOP activated the intrinsic apoptotic pathway through the increased expression of BAX (Bcl- 2-associated X protein) and the inhibition of Bcl-2 (B-cell lymphoma 2), leading to cell apop- tosis (Figure 1A).49 Moreover, ER stress inhibits the sterol regulatory element binding transcrip- tion factor (SREBF), which stimulates the tran- scription of steroid-regulated genes.49 There-
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MITOTANE TREATMENT IN ADRENOCORTICAL CARCINOMA
ALTIERI
fore, the inhibition of SREBF induce a down- regulation of steroidogenesis (Figure 1A).49 The effect of mitotane on steroidogenesis is caused by the direct suppression of steroid production in the adrenocortical cells47, 49 and by modifica- tion of the peripheral metabolism of cortisol.52 Mitotane can affect different cytochrome P450 (CYPs)-dependent mitochondrial enzymes in- volved in steroidogenesis both at the transcrip- tional and functional levels. It has been demon- strated that mitotane could inhibit the expression of the steroidogenic acute regulatory protein (StAR),53-55 the cholesterol side-chain cleav- age enzyme (P450scc, or 20,22-desmolase, en- coded by CYP11A1),53-56 the 3ß-hydroxysteroid dehydrogenase (HSD3B2),47, 55, 57 the steroid 21-hydroxylase (CYP21A2),47, 55, 57 as well as the 11ß-hydroxylase (CYP11B1)47, 58-61 (Figure 1B). Data regarding an inhibition of the steroid 17a-hydroxylase/17,20 lyase (CYP17A1) and the 18ß-hydrolase (aldosterone synthase, encod- ed by CYP11B2) by mitotane are scant.47, 56 The inhibition of all these genes results to a reduction of steroid production, including cortisol, andro- gens, and dehydroepiandrosterone.62 Moreover, mitotane can also directly bind different CYPs, including CYP11A1 and CYP11B1.63-65 How- ever, it has been showed that the direct binding with these two CYPs is not essential to induce mitochondrial dysfunction.47, 60, 63, 66 Particularly, the modulation of CYP11B1 in the adrenocorti- cal H295R cells did not affect mitotane action.60 Although the specific mechanisms of mitotane
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action are not fully understood, the high expres- sion of the steroidogenic enzymes, as well as of enzymes involved in the cholesterol metabolism in the cells of the adrenal cortex could explain its action on the adrenal glands. Mitotane also causes changes in cortisol catabolismdue to suppression of 5alpha-and 20beta-reduction, together with induction of 1beta- and 6-hydrox- ylation.52 Moreover, it strongly induces the CY- P3A4 enzyme, leading to acceleration of cortisol clearance.67 This effect has an important impli- cation in the management of patients treated with mitotane because all patients develop temporary adrenal insufficiency, necessitating glucocorti- coid replacement therapy. It has been showed that mitotane causes the inactivation of 50% of
administrated hydrocortisone, thus explaining why patients treated with mitotane require high- dose hydrocortisone for an effective replacement therapy and to avoid a life-threatening adrenal crisis.67 Moreover, since more than 50% of the available drugs are metabolized by the CYP3A4, a dose adjustment of different drugs is needed if assumed concomitantly with mitotane.68 The exact mitotane metabolism is unknown.69 It is a lipophilic drug with an absorption rate of 35-40% by the intestinal tract.70 Moreover, mi- totane can have an extremely long and highly variable plasma elimination half-life.71 These findings explain the reason why mitotane needs several weeks to reach a steady-state concentra- tion. Mitotane is mostly metabolized in the liver, but a small percentage is metabolized also in other tissues including adrenocortical cells.72, 73 After its absorption, mitotane undergoes to an a- or -hydroxylation. Its a-hydroxylated form 1-(o,p’-dichlorodiphenyl)-2,2 dichloroethene (o,p’-DDE) is an inactive metabolite of mitotane. The ß-hydroxylated form o,p’-dichlorodiphenyl acyl chloride (DDAC) has strong affinity for biological nucleophiles and can acylate differ- ent cellular molecules, or be rapidly transformed to 1,1-(o,p’-dichlorodiphenyl) acetic acid (o,p’- DDA) metabolite for renal excretion.46, 74 The acylation of cellular molecules by DDAC is supposed to be part of the mechanism of action of mitotane within adrenal cells.64 The issue on whether o,p’-DDA and o,p’-DDE may represent two potential predictive markers of response to mitotane treatment is still controversial, since in vitro and observational studies reported contrast- ing results.59, 75-77 However, more recent results support the hypothesis that the downstream me- tabolites may only reflect the process of mito- tane metabolism, without correlation with its antitumor effect.59 Due to its mechanisms of action, mitotane treatment is associated with many undesired adverse events.3, 35, 62, 78 The most common adverse phenomena are gastro- intestinal effects, such as diarrhea, nausea, and vomiting, which are mostly reported during the first months of therapy and correlate more with the oral dosage than with the mitotane plasma levels.35, 62, 79, 80 Also, the increase of gamma glutamyl transpeptidase and hepatic enzymes is
MITOTANE TREATMENT IN ADRENOCORTICAL CARCINOMA
very common.79, 80 On the contrary, central ner- vous system-related adverse events (including vertigo, ataxia, sleepiness, and mental impair- ment) occur more frequently when the plasma mitotane concentration is above 20 mg/L.35, 80, 81 For this reason, the monitoring of mitotane plas- ma concentration became a standard of care in expert centers with the aim to maintain the mi- totane levels within the therapeutic range (14-20 mg/L). Besides adrenal insufficiency, mitotane administration is associated with other endo- crinological toxicities and a large percentage of patients needed replacement therapy for hy- pomineralcortisolism, hypothyroidism, and hy- pogonadism, or statins treatment for hypercho- lesterolemia.35, 79, 82 These adverse events could affect the patients’ quality of life and cause the discontinuation of mitotane treatment.
Clinical predictive factors of response to mitotane therapy
Several clinical parameters have been investi- gated as potential predictive factors of response to mitotane therapy, both in the adjuvant setting and in advanced disease (Supplementary Digital Material 1: Supplementary Table I). However, only some of these parameters have been found to correlate with response to mitotane. The ESE- ENSAT ACC Guidelines recommend the admin- istration of adjuvant mitotane therapy for at least 2 years after tumor resection.3 However, in the daily clinical practice, the duration of the adju- vant treatment largely differs among the centers. Only recently, a retrospective multicenter study tried to answer the unsolved question regard- ing the optimal duration of mitotane adjuvant therapy.83 In ACC patients with low to moderate risk of recurrence, no correlation was observed between the duration of the adjuvant treatment and the frequency of recurrence, as well as no survival advantage was found in patients treated for longer than 2 years.83 These findings suggest that the adjuvant mitotane treatment might be discontinued after 2 years, limiting the toxicity associated with the therapy. The achievement of mitotane plasma levels above 14 mg/L (target levels) represents the strongest predictive fac- tor of response to therapy (Supplementary Table
I). This observation was first reported in a group of 34 patients with advanced ACC described in 1984 by van Slooten et al.84 from the University Hospital of Leiden. The authors reported a sig- nificantly increased survival time in patients with mitotane serum levels higher than 14 µg/mL (=14 mg/L) for a period of at least 6 months compared to patients with mitotane levels less than 10 µg/ mL or to those who were not treated with mito- tane (control group).84 These results were con- firmed ten years later from another study from Leiden by Haak et al., who showed that mitotane levels higher than 14 mg/L was associated with a better response to mitotane in patients with ad- vanced ACC.85 Few years later, a first prospec- tive study by Baudin et al. reported an objective tumor response only in advanced ACC patients with mitotane plasma levels above 14 mg/L.86 On the contrary, mitotane levels did not influence the risk of recurrence in patients adjuvantly treat- ed. However, this opposite result could be related to the low number is adjuvantly treated patients included in this study (N .= 11).86 In a multicenter study by Hermsen et al.76 investigating the plas- ma levels of mitotane, o,p’-DDA, and o,p’-DDE for predicting tumor response in 91 ACC patients with advanced disease, the authors found that median mitotane levels were higher in responder compared to non-responder patients. Particular- ly, mitotane levels ≥14 mg/L significantly corre- lated with a longer survival both at univariate and multivariate analysis. Moreover, the cutoff value of 14 mg/L was associated with a sensitivity of 65% and specificity of 69% to identify respond- ers vs. non-responders.76 This evidence was also confirmed by more recent studies both in patients adjuvantly treated with mitotane81, 87, 88 as well as in patients with advanced disease.88, 89 Therefore, the aim of the treatment is to reach a mitotane blood level at or above the target levels.3 How- ever, mitotane is a slow acting drug and the la- tency of its efficacy is related to the time needed to attain plasma target concentrations. For this reason, in patients with good performance status it is recommended to use a high-dose mitotane starting regimen that allows more patients to reach the target levels within the first 7 weeks of treatment compared to those treated with a low- dose starting regimen.80 This recommendation
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MITOTANE TREATMENT IN ADRENOCORTICAL CARCINOMA
ALTIERI
is also supported by the fact that no difference in mitotane toxicity has been observed between low-dose and high-dose regimens.80 Therefore, both regimens could both be safely used in ACC patients based on the clinical scenario and the patients’ condition.3, 80, 90, 91 To note, in most Ital- ian centers mitotane is administered following the low-dose protocol with minimal variations in the starting dose (1-2 g/day) and an increased dose every 4-7 days up to the maximal tolerated dose.87 On the other hand, contrasting results are reported on the role of mitotane metabolites levels as potential predictive factors of response to therapy (Supplementary Table I). It has been shown that high o,p’DDA and o,p’DDE levels could be associated with response in patients. 75, 76 However, these results were not confirmed in vi- tro.59 Recently, two retrospective studies39, 40 and one case report92 investigating the efficacy of mitotane in advanced-stage ACC patients dem- onstrated that a low tumor burden, considered as less then10 tumoral lesions, or as a single site of metastasis or as a low volume disease (<3 cm), is a good predictive factor of response to mito- tane (Supplementary Table I). Also, the time of disease recurrence seems to have a role in the clinical outcome. However, evidence is weak and often shows contrasting results (Supplemen- tary Table I). A late recurrence occurring more than 360 days after the primary diagnosis seems to be associated with a better clinical outcome.39 Another study suggested that ACC patients with a recurrence later than 24 months have a better response to mitotane therapy compared to those with earlier progression.88 However, a complete response to mitotane therapy has been observed also in patients who had earlier recurrence.40, 92 The primary tumor hormone secretion does not seem to be associated with response to mitotane treatment (Supplementary Table I).39, 93, 94 In contrast to that, two French studies evaluating relatively large cohorts of ACC patients from the Cochin Hospital showed that mitotane treatment increased the survival rates in the subgroup of patients with cortisol-secreting tumor compared to those not treated.95, 96 On the other hand, it has been speculated by some authors that, in advanced disease, inactive tumors may respond better to mitotane therapy.40 Finally, a metabolic
response on fluorodeoxyglucose-fused positron emission tomography (FDG-PET) scan more rapid than the radiological response on com- puted tomography (CT), as observed in a case of 52-year-old male patients with advanced dis- ease and treated with mitotane monotherapy,93 suggests than changes in metabolic activity on FDG-PET might be use predict the response to mitotane therapy, similarly to specific chemo- therapeutic drugs in other cancer types.97 Very recently, Allegra et al. investigated the role of sex on mitotane pharmacokinetics in patients adjuvantly treated.98 The authors reported that women had lower plasma mitotane and o,p’- DDE concentrations and had a higher risk to not reach the target levels above 14 mg/L, suggest- ing that female patients could be at higher risk of treatment failure.98 However, no significant dif- ference in terms of RFS and OS was observed between males and females.98
Molecular predictive markers of response to mitotane treatment
Only few molecular markers have been pro- posed to predict mitotane levels in patients with ACC and their response to treatment (Table I).49, 88, 99-104 However, none of these markers has been validated for the daily clinical practice. The first described potential markers of response was proposed by Volante et al.99 In this study, the authors evaluated the expression of the ribo- nucleotide reductase large subunit 1 (RRMI) and excision repair cross complementation group 1 (ERCCI) as potential markers of response to mitotane. They showed that low RRMI expres- sion was associated with an improved disease- free survival in ACC patients treated adjuvantly with mitotane (Table I).49, 88, 99-104 The authors suggested that RRM1 could interfere in vitro with mitotane metabolism, inducing sensitivity to mitotane in adrenocortical mitotane-insensi- tive SW-13 cells, but not in the NCI-H295R cell line.99 However, a recent in-vitro study did not confirm the correlations between RRMI expres- sion and mitotane sensitivity in primary ACC cell culture.100 No correlation was found between ERCCI expression and mitotane treatment.99 As mentioned above, SOAT1 is a key molecular
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MITOTANE TREATMENT IN ADRENOCORTICAL CARCINOMA
| TABLE I .- Investigated potential molecular predictive markers of response to mitotane therapy. | ||||
|---|---|---|---|---|
| Investigated clinical parameter | Type of treatment | Predictive markers of response to therapy | Comments | References |
| RRM1 | Adjuvant | Contrasting results (deriving also from in vitro studies) | Low RRM1 expression is associated with an improved disease-free survival | Volante et al.99 van Koetsveld et al.100 |
| SOAT1 | Adjuvant and advanced disease | No | Only one study showed that high SOAT1 expression was associated with a longer TTP | Sbiera et al.49 Weigand et al.101 van Koetsveld et al.100 |
| CYP2B6*6 SNP | Adjuvant and advanced disease | Yes (moderate evidence) | The CYP2B6*6 minor allele correlates with higher mitotane plasma levels | D'Avolio et al.102 Altieri et al.88 |
| CYP2W1 | Adjuvant and advanced disease | Yes (weak evidence) | CYP2W1 staining correlated with the response to mitotane | Ronchi et al.103 van Koetsveld et al.100 |
| CYP2W1*6 SNP | Advanced disease | Yes (moderate evidence) | The CYP2WI*6 minor allele is associated with a less frequently to achieve the mitotane target levels, with a shorter TTP and lower DCR | Altieri et al.88 |
| CYP2C19*2 SLCOIB1 699A>G SLCO1B3 571T>C | Not specified | Not evaluated | Minor allele of these enzymes reduced mitotane clearance | Yin et al.104 |
| CYP: cytochrome P450; DCR: disease control rate; RRM1: ribonucleotide reductase large subunit 1; SOAT1: sterol-O-acyl-transferase 1; SNP: single nucleotide polymorphism; TTP: time progression under mitotane therapy. | ||||
target of mitotane action.49 That is why the in- vestigation of the use of SOAT1 expression as a potential prognostic marker of response to mito- tane treatment is of particular relevance. In a first analysis, a high SOAT1 expression evaluated by immunohistochemistry was significantly associ- ated with a longer time to progression (TTP) in patients treated with mitotane both as adjuvant and in advanced disease.49 Unfortunately, this result has not been confirmed by further studies. In a recent multicenter validation study including a large cohort of ACC patients (N .= 231) treated with mitotane monotherapy SOAT1 expression did not correlate with response to treatment both in patients adjuvantly treated and in those with advanced disease, as well as with disease-spe- cific survival in both setting (Table I).49, 88, 99-104 Moreover, in primary ACC cells SOAT1 expres- sion did not correlate with mitotane sensitivity.100 Therefore, SOAT1 should be considered as a target of mitotane action rather than a marker of therapy response. Other studies focused their at- tention on different members of the cytochrome P450 (CYP) superfamily (Table I).49, 88, 99-104 The CYP superfamily is the most important enzyme
system involved in drug biotransformation, and even though the exact mechanism of mitotane metabolism is unknown, several CYPs might be implicated in its pharmacokinetics. Moreover, single nucleotide polymorphism (SNP) of these CYPs might affect the protein function, causing an impaired ability to metabolize different drugs. CYP2B6 is one of the most important CYP in- volved in the metabolism of mitotane.105 In a se- ries of 27 patients with ACC adjuvantly treated with mitotane, the CYP2B6*6 minor allele corre- lated with higher mitotane plasma levels during the first 3 and 6 months of therapy compared to patients with CYP2B6*6 major allele.102 Another CYPs that could be potentially involved in the metabolism of mitotane is CYP2W1. This en- zyme is involved in the metabolism of lysophos- pholipids and is highly expressed in normal adre- nal glands and adrenocortical tumors.103 A signif- icant correlation has been demonstrated between CYP2W1 staining in ACC and the patients’ re- sponse to mitotane therapy, both in an adjuvant setting and in advanced disease.103 This correla- tion was also confirmed in vitro, where CYP2W1 resulted to be a predictor of mitotane sensitiv-
MITOTANE TREATMENT IN ADRENOCORTICAL CARCINOMA
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ity.100 A recent large multicenter ENSAT study including 182 ACC patients treated with mito- tane monotherapy as first line of medical treat- ment both in an adjuvant setting and in advanced disease evaluated the correlation between CY- P2W1*6 (rs3808348, p.P448L) and CYP2B6*6 (rs3745274, p.Q171H) SNPs with the response to mitotane evaluated as TTP and disease control rate (DCR).88 CYP2W1*6 and CYP2B6*6 minor allele frequency in the investigated cohort was 15% and 26%, respectively. In the subgroup of patients with non-completely resectable, recur- rent, or advanced ACC (N .= 79), a slightly in- creased risk of mitotane levels under the thera- peutic target and a significantly increased risk of shorter TTP and lower DCR was identified for carriers of the minor (T) allele of CYP2W1*6. On the other hand, patients with the CYP2B6*6 minor (T) allele achieved the therapeutic range more frequently, particularly when associated with the major CYP2W1*6 allele.88 However, the potential role of those SNPs as predictive mark- ers of mitotane therapy were not found in patients adjuvantly treated with mitotane (N .= 103).88 It has been speculated that the tumoral expres- sion of CYP2W1103 and CYP2B6106 might be responsible for a local metabolism of mitotane in case of non-completely resectable, recurrent, or advanced ACC, correlating with the response to therapy. Therefore, we could speculate that CYP2B6*6 and CYP2W1*6 SNP might represent valuable biomarkers that could be used to predict the mitotane plasma levels. However, these re- sults should be confirmed by larger and prospec- tive studies. A recent population pharmacokinet- ics study based on a two-compartment model in 48 patients with ACC identified that genetic vari- ants of the CYP2C19*2 and of two transporters for drug uptake in the liver SLCO1B1 699A>G and SLCO1B3 571T>C, together with the lean body weight at the start of treatment, significant- ly influenced mitotane clearance.104 Particularly, the CYP2C19*2 and the SLCO1B1 699A>G mi- nor allele reduced mitotane clearance by 44.9% and 39.9%, respectively. While heterozygote and homozygote carriers of SLCO1B3 571T>C had a reduced mitotane clearance of 40.2% and 30.2%, respectively.104 In this study, CYP2B6*6 was not found to be associated with mitotane pharmaco-
kinetics, whereas CYP2W1*6 was not investigat- ed.104 However, the authors did not evaluate the potential use of these SNPs as potential markers of response to mitotane treatment.104
Conclusions
ACC is a rare and aggressive malignancy with high risk of recurrence even after complete surgi- cal tumor resection.32-34 The currently available therapeutic options are limited.29 Mitotane has been the cornerstone of the adjuvant therapy in patients with high risk of recurrence.3, 31 How- ever, except for the ADIUVO study,38 the use of mitotane is based on retrospective and occa- sionally conflicting evidence. On the other hand, mitotane represents the first line of medical treat- ment in advanced-stage ACC patients with low grade disease and limited metastatic burden.3, 31 However, the treatment with mitotane continues to represent to date a clinical challenge since its exact mechanism of action is still unknown and potential clinical and molecular markers of mitotane efficacy are missing. Different clini- cal markers predicting the response to mitotane have been proposed. Maintaining the mitotane plasma levels within the target range of 14 to 20 mg/L represents the strongest predictor of mito- tane effectiveness both in the adjuvant and the advanced-stage settings.76, 81, 87-89 Furthermore, in advanced cases, low tumor burden seems to be associated with a better mitotane response.39, 40, 92 Other clinical parameters, such as the late recur- rence after primary ACC diagnosis and chang- es in metabolic activity on FDG-PET, are only weakly associated with mitotane response, 39, 88, 93 whereas other parameters completely failed as predictive markers.39, 40, 59, 76, 83, 93 Similar to the clinical parameters, reliable molecular mark- ers predicting the response to mitotane are cur- rently missing. SOAT1, which plays a key role in the mechanism of mitotane action,49 is now considered as a target of mitotane rather than a marker of therapy response.101 More promising results are coming from the investigation of the CYP2W1*6 and CYP2B6*6 SNPs, which cor- relate with the achievement of the mitotane tar- get levels as well as with the response to thera- py.88, 100, 102 However, none of these markers has
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MITOTANE TREATMENT IN ADRENOCORTICAL CARCINOMA been validated for clinical use yet. In conclusion, a better insight into the molecular mechanisms of action of mitotane as well as the potential use of clinical parameters and molecular markers pre- dicting the individual response to mitotane are urgently needed. References 1. Kerkhofs TM, Verhoeven RH, Van der Zwan JM, Diele- man J, Kerstens MN, Links TP, et al. Adrenocortical carci- noma: a population-based study on incidence and survival in the Netherlands since 1993. Eur J Cancer 2013;49:2579-86. 2. Fassnacht M, Libé R, Kroiss M, Allolio B. Adrenocorti- cal carcinoma: a clinician’s update. Nat Rev Endocrinol 2011;7:323-35. 3. Fassnacht M, Dekkers OM, Else T, Baudin E, Berruti A, de Krijger R, et al. European Society of Endocrinology Clini- cal Practice Guidelines on the management of adrenocorti- cal carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2018;179:G1-46. 4. Fassnacht M, Johanssen S, Quinkler M, Bucsky P, Wil- lenberg HS, Beuschlein F, et al .; German Adrenocortical Carcinoma Registry Group; European Network for the Study of Adrenal Tumors. Limited prognostic value of the 2004 In- ternational Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Clas- sification. Cancer 2009;115:243-50. 5. Assié G, Letouzé E, Fassnacht M, Jouinot A, Luscap W, Barreau O, et al. Integrated genomic characterization of adre- nocortical carcinoma. Nat Genet 2014;46:607-12. 6. Lippert J, Appenzeller S, Liang R, Sbiera S, Kircher S, Altieri B, et al. Targeted Molecular Analysis in Adrenocor- tical Carcinomas: A Strategy Toward Improved Personalized Prognostication. J Clin Endocrinol Metab 2018;103:4511-23. 8. Marquardt A, Landwehr LS, Ronchi CL, di Dalmazi G, Riester A, Kollmannsberger P, et al. Identifying New Poten- tial Biomarkers in Adrenocortical Tumors Based on mRNA Expression Data Using Machine Learning. Cancers (Basel) 2021;13:4671. 9. Ronchi CL, Sbiera S, Altieri B, Steinhauer S, Wild V, Bekteshi M, et al. Notch1 pathway in adrenocortical carcino- mas: correlations with clinical outcome. Endocr Relat Cancer 2015;22:531-43. 10. Sbiera S, Sbiera I, Ruggiero C, Doghman-Bouguerra M, Korpershoek E, de Krijger RR, et al. Assessment of VAV2 Expression Refines Prognostic Prediction in Adrenocortical Carcinoma. J Clin Endocrinol Metab 2017;102:3491-8. 11. Liang R, Weigand I, Lippert J, Kircher S, Altieri B, Stein- hauer S, et al. Targeted gene expression profile reveals CDK4 as therapeutic target for selected patients with adrenocortical carcinoma. Front Endocrinol (Lausanne) 2020;11:219. 12. Landwehr LS, Altieri B, Schreiner J, Sbiera I, Weigand I, Kroiss M, et al. Interplay between glucocorticoids and tumor- infiltrating lymphocytes on the prognosis of adrenocortical carcinoma. J Immunother Cancer 2020;8:e000469. 13. Bilimoria KY, Shen WT, Elaraj D, Bentrem DJ, Win- Vol. 47 - No. 2 to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher. This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically 7. Zheng S, Cherniack AD, Dewal N, Moffitt RA, Danilova L, Murray BA, et al .; Cancer Genome Atlas Research Net- work. Comprehensive Pan-Genomic Characterization of Ad- renocortical Carcinoma. Cancer Cell 2016;29:723-36.
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cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher. to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access
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Conflicts of interest .- The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.
Authors’ contributions .- Barbara Altieri has given substantial contributions to the study design and to the preparation of tables and figures; Barbara Altieri, Enzo Lalli, and Antongiulio Faggiano contributed to data collection and to the manuscript draft. All authors read and approved the final version of the manuscript.
History .- Article first published online: December 9, 2021. - Manuscript accepted: November 24, 2021. - Manuscript revised: No- vember 16, 2021. - Manuscript received: June 8, 2021.
Supplementary data .- For supplementary materials, please see the HTML version of this article at www.minervamedica.it
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